Objective: The aim of this study is to explore whether the inhibition of GluN2D-containing NMDA receptors (NMDAR2D) can delay the pathological manifestations of Parkinson’s disease (PD).

Background: NMDA receptor is a kind of ionotropic glutamate receptors with high Ca²⁺ permeability, and its GluN2D subunit is mainly distributed in midbrain region, especially in substantia nigra, striatum and subthalamic nucleus. Previous studies have revealed that the distribution of GluN2D subunit on the cell membrane increased significantly in PD animal models. However, it remains unknown whether the blockade of NMDAR2D has neuroprotective efficacy in PD.

Method: Cell viability assay and flow cytometry were performed for evaluating the effects of GluN2D modulators in 6-OHDA-treated MES23.5 dopaminergic neurons. Rotational behavioral test and gait analysis were used to assess motor impairment in 6-OHDA-lesioned rats. HPLC analysis, and immunohistochemistry were used to measure nigrostriatal degeneration.

Results: The allosteric enhancer of NMDAR2D, CIQ, can decrease the cell viability of MES23.5 cells, while the inhibitor, QNZ46, significantly improve the cell viability and mitochondrial function of 6-OHDA-treated cells. We also verified the neuroprotective effect of QNZ46 in vivo, which significantly rescue the dopaminergic cell loss, abnormal behaviors induced by 6-OHDA.

Conclusion: Considering the vital role of mitochondrial dysfunction in PD, inhibition of NMDAR2D may be a considerable way to treat this disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/inhibition-of-glun2d-containing-nmda-receptors-alleviates-the-loss-of-dopaminergic-neurons-and-behavioral-deficits-in-6-ohda-induced-model-of-parkinsons-disease/